Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase

Abstract

The present disclosure discloses compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and/or the treatment of diseases and disorders associated with defects in NAD+ biosynthesis, e.g., metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with ageing. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament.

The invention claimed is: 
     
       1. A compound represented by Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or tautomer thereof, wherein: 
         X is O or OR h ; 
         W is N; 
         L is —SCH 2 —; 
         R 1  is absent, C 6 -C 10  arylene or heteroarylene, wherein the heteroarylene comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10  arylene and heteroarylene are unsubstituted or substituted with one to two R e ; 
         each R 6  is independently at each occurrence H or C 1 -C 4  alkyl; 
         R 7  is A; 
         A is —(C(R 6 ) 2 ) r tetrazole; 
         R c  is H, halogen, or —CN; 
         R d  is —CF 3 , —CR f F 2 , —(C(R 6 ) 2 ) t —C 6 -C 10  aryl, —(C(R 6 ) 2 ) t -5- or 6-membered heteroaryl; 
         each R e  is independently at each occurrence C 1 -C 6  alkyl, halogen, C 1 -C 6  haloalkyl, —NHR z , —OH, or —CN; 
         R f  is H; 
         R h  is H; 
         R j  is absent; 
         R z  is H, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
         each r is independently 0, 1, or 2; 
         each t is independently 1 or 2; and 
            represents a single bond or a double bond. 
       
     
     
       2. The compound of  claim 1 , wherein R c  is H. 
     
     
       3. The compound of  claim 1 , wherein R e  is —CN. 
     
     
       4. The compound of  claim 1 , wherein R d  is —CF 3 . 
     
     
       5. The compound of  claim 1 , wherein R d  is —CR f F 2 . 
     
     
       6. The compound of  claim 1 , wherein R d  is —(C(R 6 ) 2 ) t —C 6 -C 10  aryl or —(C(R 6 ) 2 ) t -5- or 6-membered heteroaryl. 
     
     
       7. The compound of  claim 6 , wherein R d  is —CH 2 -C 6 -C 10  aryl. 
     
     
       8. The compound of  claim 1 , wherein R 1  is C 6 -C 10  arylene. 
     
     
       9. The compound of  claim 1 , wherein R 1  is heteroarylene. 
     
     
       10. The compound of  claim 1 , wherein R 1  is absent. 
     
     
       11. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                 
                   Cpd No. 
                   Structure 
                 
                     
                 
                   I-26 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   I-29 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   I-32 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   I-34 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       12. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of: